Currently, some derivatives of nitrogenous bases are used as therapeutic drugs for the treatment and prevention of various viral infections, in particular infections caused by herpes virus, including the combination therapy of HIV-infected and cancer patients, and of patients with organ transplants. For example, guanine derivatives are used as antiviral therapeutic drugs, in particular for the treatment of infections caused by herpes virus.
Herpes is the most common human disease, the causative agent of which is herpes virus. There are known eight types of herpes viruses, the best known being herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2), Varicella-Zoster virus (HHV-3), Epstein-Barr virus (HHV-4), cytomegalovirus (HHV-5), and some others. Considerable part of population in the world is infected with herpes viruses in the form of latent infection. The herpes virus permanently exists in the nerve cells of the infected person, but the disease manifests itself clinically only during the exacerbation period, i.e. the period of active reproduction of the pathogen. HSV-1 is the cause of diseases such as keratitis, “cold on the lips,” and encephalitis; HSV-2 causes genital infection; HHV-3 causes Varicella Zoster and shingles diseases; HHV-4 is the cause of infectious mononucleosis; and HHV-5 is the cause of cytomegaloviral hepatitis, colitis, and pneumonitis.
The therapeutic drugs used in order to treat diseases caused by herpes viruses are those capable of effectively suppressing the symptoms of virus infection, virus reproduction and development if received regularly. One such widely used therapeutic drug is acyclovir, which is a derivative of guanine and which inhibits the reproduction of the virus in cells. However, acyclovir is efficient in inhibiting virus reproduction when used in high doses; in particular the amount of this therapeutic drug for ingestion is up to 4,000 mg/day. Increasing one-time acyclovir dose reduces its bioavailability, and this can give rise to medicamental toxic effects on the body. One more disadvantage of acyclovir consists in its low water solubility: 1.3 mg/mL at 25° C. and 2.5 mg/mL at 37° C.; and moreover acyclovir is almost insoluble in hydrophobic systems. For this reason, acyclovir ingestion gives rise to some probability that fine crystals would form in the urea (see Mason, W. J., and Nickols H. H., “Crystalluria from acyclovir use,” N. Engl. J. Med., 2008, 358: e14) and that nefrotoxicity would appear. In addition, acyclovir-resistant herpes virus strains have recently appeared with ever increasing frequency, especially in immunocompromised people.
Valacyclovir is a modified species of acyclovir and has higher activity and bioavailability: 54% against 15-20% for acyclovir. Nonetheless, valacyclovir, as acyclovir, is efficient only in high doses of 1,000 to 4,000 mg/day.
Other guanine derivatives, for example pencyclovir and gancyclovir, are also known to have activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), Varicella-Zoster virus, Epstein-Barr virus, and cytomegaloviral infections and to be useful for the treatment and prevention of infections caused by these viruses, in particular for the treatment and prophylaxis of immunocompromised persons, for example AIDS patients, cancer patients, and those with organ transplants. One common drawback of pencyclovir and gancyclovir consists in their moderate water solubilities (0.17% for pencyclovir and 0.43% for gancyclovir) and low bioavailabilities (1.5% and 5%, respectively).
Antiviral therapeutic drugs shall have the following properties: the ability to penetrate a cell, minimal cytotoxicity, selectivity, non-addictivity, and non-accumulation in the body. Therefore, one line in dosage form design consists in searching for compounds that would improve the antiviral activity of prior-art therapeutic drugs when formulated therewith. The patent EP 0477871 (1992, IPC: A61K 31/52) discloses an antiviral composition having selective and synergistic activity against herpes simplex virus types 1 and 2. That antiviral composition consists of at least two compounds which are derivatives of guanine: oxetanocin G (OXT-G), acyclovir (ACV), and carbocyclic oxetanocin G (C-OXT-G).

The effect of those antiviral compositions on the reproduction of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) was studied in Vero cell cultures. Monolayer Vero cell cultures were grown in Eagle's nutrient medium supplemented with 10% calf serum at a temperature of 37° C. Afterwards, the cultures were infected with HSV-1 and HSV-2. Then, guanine derivatives were inserted into the culture medium of infected cells either individually or in combinations with each other, and the concentrations that provided the 50% inhibition of the virus-induced cytopathic effect (ID50) were determined. The compositions consisting of two compounds were shown to reach the ID50 values at lower concentrations than those required for each of the individual components. For example, the combination of acyclovir (0.04-0.4 mcg/mL) with oxetanocin G (0.4-5.4 mcg/mL) or with carbocyclic oxetanocin G (0.01-0.2 mcg/mL) provides a synergistic effect against HSV-1, and the combination of acyclovir (0.1-3.4 mcg/mL) with oxetanocin G (0.4-4 mcg/mL) or with carbocyclic oxetanocin G (0.04-0.54 mcg/mL) provides a synergistic effect against HSV-2.
The Russian Federation patent 2240792 (2004, IPC: A61K 31/40) claims compositions comprising netropsin or a bis-derivative thereof with acyclovir and gancyclovir, these compositions providing high antiviral activity levels against herpes simplex viruses type 1 (HSV-1).

Combinations of netropsin compounds with acyclovir and gancyclovir provide an appreciable enhancement of the antiherpetic activity compared to each of the combined antiviral agents taken individually. For example, for the combined used of netropsin (2.5 mcg/mL) and bis-netropsin (0.15 mcg/mL) with acyclovir, the 50% inhibition of the virus-induced cytopathic effect is achieved for acyclovir concentrations of 0.075 mcg/mL and 0.15 mcg/mL, which is, respectively, five and three times lower than the concentration of acyclovir used alone (0.4 mcg/mL). A combination of netropsin and bis-netrospin with gancyclovir provides a fivefold reduction in gancyclovir concentration.
The U.S. Pat. No. 6448227 (2002, IPC: A61K 38/00) discloses a mixture containing S-acetyl glutathione and acyclovir as an agent against a herpes simplex virus or Varicella-Zoster virus. Glutathione is a tripeptide γ-glutamyl cysteinyl glycine.

S-acetyl glutathione was shown to be an efficient agent against a herpes simplex virus (HSV-1) starting with concentrations of 0.35 mg/mL; acyclovir is especially efficient in concentrations of 0.45 mcg/mL. The combination of S-acetyl glutathione and acyclovir gives rise to a strong synergistic effect against HSV-1. For example, when S-acetyl glutathione (0.7 mg/mL) is used with acyclovir (0.45 mcg/mL), the virus titer is not determined.
Compositions of S-acetyl glutathione (0.35 mg/mL) with three acyclovir concentrations were shown to cause a noticeable synergistic effect against Varicella-Zoster virus, which was especially strong when the acyclovir concentration was 0.9 mcg/mL.
The Russian Federation patent 2104032 (1998, IPC: A61K 47/22) discloses a method for enhancing the efficiency of therapeutic drugs by means of organogermanium compounds (derivatives of germatrane). Organogermanium compounds were shown to enhance the activity of many known antiviral therapeutic drugs, such as adamantane derivatives (methadone and rimantadine), nucleoside analogues (acyclovir, gancyclovir, vidarabine, and idoxuridine), thiosemicarbazone derivatives (methisazone), and foscarnet. The therapeutic index increases fourfold with the simultaneous reduction of toxicity and alleviation of side effects. The antiviral activity of compositions consisting of germatrane derivatives with foscarnet or acyclovir was assayed in male guinea pigs infected with Herpes simplex virus HSV-2. Clinical studies showed that the use of germatrane derivatives formulated with foscarnet or acyclovir provided a twofold to fourfold enhancement in the effect of the latter in the treatment of HSV-2.
The German Patent 10343365 (2005, IPC: A61K 45/00) claims pharmaceutical compositions of xanthogenates (dithiocarbonates) in combination with antiviral therapeutic drugs for the treatment of viral diseases. Xanthogenates, especially tricyclodecan-9-yl-xanthogenate (D609), are well known for their antiviral and antitumor activity.

The use of xanthogenates as antiviral therapeutic drugs is complicated by the fact that high concentrations of these agents are required for treating living bodies. The last-cited patent demonstrates that the use of xanthogenate derivatives, such as D609, in combination with acyclovir results in an enhancement of antiviral activity. In the presence of low, inefficient concentrations of xanthogenate, the activity of acyclovir in a cell culture increased fivefold. In experiments on living bodies, the combination of D609 and acyclovir provided the survival of all animals infected with HSV-1.
It follows that the way used in the prior art for improving the antiviral activity of known therapeutic drugs involved the preparation of antiviral compositions comprising several active compound that enhanced the antiviral effect of the therapeutic drug.
The authors of this invention propose a radically different approach to improve the antiviral activity of known compounds. What is claimed according to the invention is: germanium complex compounds with derivatives of purine nitrogenous bases, hydroxycarboxylic acids, and amino acids, wherein these germanium complex compounds are individual chemical compounds having improved biopharmaceutical values, in particular high water solubilities, compared to the relevant purine nitrogenous base derivatives, and having higher antiviral activities than the relevant purine nitrogenous base derivatives.